Excitation-contraction coupling in ventricular myocytes is enhanced by paracrine signaling from mesenchymal stem cells

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• 作者：J. DeSantiago^a ; ^{jdesant@uic.edu} ; D.J. Bare^a ; ^{dbare@uic.edu} ; I. Semenov^d ; R.D. Minshall^c ; D.L. Geenen^a ; ^{geenen@uic.edu} ; B.M. Wolska^a ; ^b ; ^{bwolska@uic.edu} ; K. Banach^a ; ^{kbanach@uic.edu}
• 关键词：Mesenchymal stem cells ; Excitation contraction coupling ; Akt ; Ca imaging ; Paracrine signaling ; Nitric oxide synthase
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2012
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：June, 2012
• 卷：52
• 期：6
• 页码：1249-1256
• 文件大小：1315 K

摘要

In clinical trials mesenchymal stem cells (MSCs) are transplanted into cardiac ischemic regions to decrease infarct size and improve contractility. However, the mechanism and time course of MSC-mediated cardioprotection are incompletely understood. We tested the hypothesis that paracrine signaling by MSCs promotes changes in cardiac excitation-contraction (EC) coupling that protects myocytes from cell death and enhances contractility. Isolated mouse ventricular myocytes (VMs) were treated with control tyrode, MSC conditioned-tyrode (ConT) or co-cultured with MSCs. The Ca handling properties of VMs were monitored by laser scanning confocal microscopy and whole cell voltage clamp. ConT superfusion of VMs resulted in a time dependent increase of the Ca transient amplitude (ConT_15min: 螖F/F₀ = 3.52 卤 0.38, n = 14; Ctrl_15min:飥?螖F/F₀ = 2.41 卤 0.35, n = 14) and acceleration of the Ca transient decay (蟿: ConT: 269 卤 18 ms n = 14; vs. Ctrl: 315 卤 57 ms, n = 14). Voltage clamp recordings confirmed a ConT induced increase in I_Ca,L (ConT: 鈭?#xA0;5.9 卤 0.5 pA/pF n = 11; vs. Ctrl: 鈭?#xA0;4.04 卤 0.3 pA/pF, n = 12). The change of 蟿 resulted from increased SERCA activity. Changes in the Ca transient amplitude and 蟿 were prevented by the PI3K inhibitors Wortmannin (100 nmol/L) and LY294002 (10 渭mol/L) and the Akt inhibitor V (20 渭mol/L) indicating regulation through PI3K signal transduction and Akt activation which was confirmed by western blotting. A change in 蟿 was also prevented in eNOS^{鈭?鈭?/sup> myocytes or by inhibition of eNOS suggesting an NO mediated regulation of SERCA activity. Since paracrine signaling further resulted in increased survival of VMs we propose that the Akt induced change in Ca signaling is also a mechanism by which MSCs mediate an anti-apoptotic effect.}